MXPA98003636A - Fluoxet enteric granules - Google Patents

Abstract

The present invention relates to a superior enteric formulation of an antidepressant drug, fluoxetine, which is in the form of enteric granules in which the enteric layer comprises hydroxypropylmethyl cellulose succinate

Description

FLUOXETINE ENTRERIC GRANULES DESCRIPTION OF THE INVENTION This invention pertains to the field of pharmaceutical science, and provides a superior enteric formulation of the anti-depressant drug, fluoxetine. Fluoxetine (N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine) is an antidepressant drug which is described, for example, in U.S. Patent Nos. 4,314,081 and 4,626,549. The action of fluoxetine is based on its ability to selectively inhibit serotonin uptake by neurons in the central nervous system. In the USA. and in many other countries fluoxetine is indicated for the treatment of depression, obsessive-compulsive disorders and bulimia. In the USA, currently available pharmaceutical forms of fluoxetine, in the form of the hydrochloride salt, include capsules and a solution. In the U.S. patent No. 4,314,081 (column 16, lines 52-55) a tablet formulation of compounds of the fluoxetine type is also contemplated. More recently, a dispersible tablet has been described (see Patent Application Publication EP 693,281). In the U.S. patent No. 4,847,092 a sustained release formulation of fluoxetine is claimed In US Patent No. 4,444,778 (column 6, line 10 et seq.) Serotonin uptake inhibitor tablets are contemplated which have been REF: 27307 covered "to retard absorption and disintegration to" provide a sustained duration over a longer period ". In WO 92/13452 (controlled release and sustained release - page 19) and in U.S. Pat. No. 5,356,934 (column 4) formulations of R-Fluoxe ina are generally contemplated. Similar teachings are established for S-fluoxetine in U.S. Pat. No. 5,104,899. Enteric pharmaceutical formulations are manufactured so that the product passes unchanged through the patient's stomach and dissolved, and releases the active ingredient rapidly when it leaves the stomach and enters the small intestine. Such formulations are used for a long time, and are conventionally in the form of tablets or granules, where the active ingredient is in the innermost part of the tablet or granule and is put into a film or wrap "the enteric coating", which is insoluble in acidic environments, such as the stomach, but soluble in close to neutral environments such as the small intestine. Some difficulties have arisen in the conventional preparation of enteric formulations of fluoxetine. In particular, it was found that fluoxetine reacts with some enteric coatings to form a slowly soluble or even insoluble coating. Similar reactions have been observed with enteric coatings "with other drugs -duloxetine, nortriptyline, desipramine, sertraline and paroxetine.Duloxetine, subjected to a clinical evaluation as an antidepressant candidate, is (+) -N-methyl-3- (1-naphthalene). -iloxy) -2-thiophenpropanamine, and is commonly used as its hydrochloride salt.A enteric coating formulation of duloxetine is claimed in US Patent No. 5,508,276 to prevent acid degradation of the compound in the stomach. It has been observed that, due to the long half-life of fluoxetine, other dosage regimens other than the daily dosage are effective, especially for a maintenance dosage. For example, Burke, and col .. Psvchopharmacol. Bull., 31 (3), 524 (1995) reported that 60 mg of fluoxetine hydrochloride given once a week were as effective as 20 mg per day during maintenance therapy (ie, after eight weeks of daily dosing) . Montgomery, v. Col., Eur. Arch. Psvchiatrv Clin. Neuroscience, 244 (4), 211 (1994) reported that 120 mg of fluoxetine dosed biweekly were not effective for the treatment of recurrent brief depression. Benazzi, v. Col., Pharmacopsychiatry, 27 (6), 246 (1994) advocated twenty milligrams per week of fluoxetma, for the reduction of the secondary effects of sexual dysfunction. Although previous studies employed single or multiple capsules of 20 mg to provide the indicated therapy, 60 mg capsules of fluoxetine hydrochloride are available in, for example, South Africa for the treatment of bulimia due to the long half-life of fluoxetine, there is currently no need to prepare a formulation of higher depreciation.Although these higher doses of fluoxetine have been shown to be effective, there may be associated side effects, such as nausea, presumably due to local irritation or increase of plasma levels shortly after dosing.Therefore, it has now been appreciated that a formulation containing large doses of fluoxetine (eg, 60-120 mg) that blunts the initial release of fluoxetine will have clinical advantages, i.e. Such formulations not only provide a convenient and effective dosage once a week, but have as a benefit less side effects. Thus, it is desired to have a formulation that can be used to provide a single convenient dose for maintenance therapy suggested by the above articles without providing an increase in unwanted side effects. The present invention has been created through efforts to solve the above and other problems, and provides a superior enteric formulation of fluoxetyria. The present invention provides an enteric fluoxetine granule comprising a) a core consisting of fluoxetine and one or more pharmaceutically acceptable excipients; b) an optional separation layer; c) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS) and a pharmaceutically acceptable excipient; d) an optional termination layer. The invention also provides a method of making an enteral fluoxetine granule comprising a) providing a core consisting of fluoxetine and one or more pharmaceutically acceptable excipients; b) optionally, applying to the core a separation layer comprising one or more pharmaceutically acceptable excipients; c) applying an enteric layer comprising HPMCAS and one or more pharmaceutically acceptable excipients, wherein HPMCAS is applied as an aqueous solution or suspension and application is made in a fluid bed type apparatus, -d) optionally, applying a layer of completion. Throughout this document, all expressions of percentage, ratio, proportion and similar, will be in units of weight unless otherwise indicated. Expressions of proportions of the enteric product will refer to the product in its dry form after separation from the water in which some of the ingredients have dissolved or dispersed. This invention contemplates formulations containing fluoxetine preferably as the hydrochloride salt however, as will be appreciated by those skilled in the art, other forms of salt or free base could be used to obtain the same beneficial effect provided by this invention. In addition, solvates of fluoxetine or its salts as well as the free base, salts and / or solvates of the individual isomers of fluoxetine, namely R-fluoxetine and S-fluoxetine are contemplated by this invention (see, for example, Robertson, et al. , J. Med. Chem. 31. 1412 (1988)). Throughout this description, unless otherwise indicated, the term "fluoxetine" contemplates all its forms, although fluoxetine hydrochloride is clearly the most preferred embodiment of this invention. When used in this description the term "sugar" refers to a sugar other than a reducing sugar. A reducing sugar is a carbohydrate that reduces the Fehling (or Benedict) or Tollens reagent. All monosaccharides are reducing sugars as are most disaccharides with the exception of sucrose. A common sugar frequently used as a binding agent or filler is lactose. This excipient is particularly useful for tablets since it compresses well, is both a binding diluent, and is inexpensive. However it is a reducing sugar and it has been discovered that fluoxetine interacts with lactose over time both at room temperature and under accelerated stability conditions (heat). Therefore, it is critical for this invention to avoid lactose and other reducing sugars for formulations comprising fluoxetine. As discussed below, sucrose is the preferred sugar. Next, several components and layers of the granule will be discussed individually, together with the methods of adding different ingredients to build the fluoxetine granule. A preferred core for the granule is prepared by applying a layer containing fluoxetine to an inert core. Such inert nuclei are conventionally used in pharmaceutical science, and are easily acquired in all industrial countries. The most preferred core is one prepared from starch and sucrose, for use in confectionery as well as in the pharmaceutical industry. However, nuclei of some pharmaceutically acceptable excipient can be used, including, for example, microcrystalline cellulose, vegetable gums, waxes and the like. The main characteristic of the inert nucleus is to be inert, with respect to both fluoxetine and the other excipients in the granule and with respect to the patient who will ultimately ingest the granule.

The size of the cores depends, of course, on the desired size of the granule to be manufactured. In general, the granules can be as small as 0.1 mm, or as large as 2 mm. Preferred cores are from about 0.3 to about 0.8 mm, to provide tablets finished in the desired range of preferred size from about 0.5 to about 1.5 mm in diameter. It is always preferred for the cores to be of a reasonably small particle size distribution, to improve the uniformity of various coatings to be added and the homogeneity of the final product. For example, the cores can be specified as being in the particle size ranges such as from 18 to 20 U.S. of mesh ', from 20 to 25 U.S. of mesh, from 25 to 30 U.S. of mesh, or 30 to 35 U.S. of mesh, to obtain distributions of acceptable size of several absolute sizes. The number of cores to be used obviously depends on the weights and the thickness of the layers added; in general, the core comprises from about 10 to about 70 percent of the product. More preferably, the core loading represents from about 15 to about 45 percent of the product. When the manufacture of the granule begins with the inert nuclei, the fluoxetine is coated on the nuclei to give a final concentration of the drug of about 10 to about 25 percent of the product, in general. The amount of fluoxetine, of course, depends on the desired dose of the drug and the amount of granules that it is desired to administer. The dose of fluoxetine is in the range of 20-100 mg (equivalent basis), more usually 80-90 mg, and the usual amount of pills is that amount which is conveniently maintained in gelatin capsules. The comparison of the volume of the gelatin capsules and the desired dose leads the pharmacist to a concentration range of about 15% to about 25% fluoxetine in the present product. Some attention should be given to the size of the fluoxetine particle. The compound can precipitate in the form of needle-like crystals that can be quite bulky. Coating the cores with fluoxetine in a needle-like manner can be difficult and it is advisable to grind or otherwise reduce the fluoxetine particle size to below about 50 μm before use in the present product and process.

A convenient way to coat the cores with fluoxetine is the "powder coating" process where the cores are wetted with a sticky liquid or binder, the fluoxetine is added as a powder, and the "mixture" is dried. It is carried out regularly in the practice of the industrial pharmacy, and the appropriate equipment is of daily use.This equipment is, in fact, used in several steps of the present procedure, and will therefore be discussed in detail here. It has been handled in conventional coating containers similar to those used in sugar coating procedures.This procedure can be used to prepare granules, but this equipment has a less efficient airflow and drying capabilities that limit application speeds and can result in a longer processing to minimize agglomerations, alternatively, the present product could be done in a team of fluidized bed (using a rotary processor), or in a turntable equipment such as the Freund CF-Granulator (Vector Corporation, Marion, Iowa). The turntable equipment typically consists of a cylinder, the bottom of which is the turntable. The movement of the mass of particles to be coated is provided by friction of the mass between the stationary wall of the cylinder and the revolving bottom thereof. Means for applying hot air to the wall to dry the dough can be provided and liquids can be sprayed onto the dough and the drying rate again balanced as in the case of the fluidized bed.

When a powder coating is applied, the mass of granules, in the present case, is kept in a sticky state, and the powder to adhere there, in this case fluoxetine, is added continuously or periodically and adheres to the sticky granules . When all fluoxetine has been applied, the spray is stopped and the mass is allowed to dry in the air stream. It may be appropriate or convenient to add some inert powders to fluoxetine.

Additional solids can be added to the layer with fluoxetine. These solids can be added to facilitate the coating process as a need to assist the flow, reduce the static load, help increase the volume and form a smooth surface. Inert substances such as talc, kaolin and titanium dioxide can be used, lubricants such as magnesium stearate, finely divided silicon dioxide, crospovidone, and non-reducing sugars, for example, sucrose. The amounts of said substances are in the range of about a few tenths of 1% of the product, up to about 20% of the product. Such solids would be of fine particle size, less than 50 μm, to produce a smooth surface. Fluoxetine is prepared to adhere to the cores by spraying a pharmaceutical excipient which is sticky and adherent when wet and when dried, a strong, coherent film. Pharmaceutical scientists are aware of this and conventionally use many of these substances, most of them polymers. Such preferred polymers include hydroxypropylmethylcellulose, hydroxypropylcellulose and polyvinylpyrrolidone. Such additional substances include, for example, methylcellulose, carboxymethylcellulose, acacia and gelatin. The amount of the adherent excipient is in the range of from about 4% to about 12% of the product, and depends largely on the amount of fluoxetine to adhere to the core. Fluoxetine can also be incorporated into the cores by spraying a suspension comprising fluoxetine suspended in an excipient solution of the fluoxetine layer, dissolved or suspended in sufficient water to make the spray suspension. Said suspension can be ground in a machine adapted for milling suspensions, to reduce the size of the fluoxetine particle. Grinding in the form of a suspension is desired because it avoids the generation of dust and the contamination problems that arise when grinding dry powder of drugs. A preferred method for applying this suspension is the conventional fluidized bed coating pharmaceutical device, such as the Wurster column, which consists simply of a vertical cylinder with an air permeable bottom and an upward spray cannula located immediately above the bottom or a downward spray cannula mounted on top of the product mass. The cylinder is loaded with the particles to be coated, a sufficient volume of air is drawn through the bottom of the cylinder to suspend the mass of particles, and the liquid to be applied is sprayed onto the mass. The temperature of the fluidizing air is balanced against the spray rate to maintain the mass of granules or tablets at the desired level of moisture and tack while the coating is formed. On the other hand, the core may comprise a monolithic particle in which fluoxetine is incorporated. Such cores can be incorporated by granulation techniques that are very widespread in pharmaceutical science, particularly in the preparation of granulated material for reduced tablets. The size of the core particles is too small for compression preparation techniques, but the nuclei can be prepared by mixing fluoxetine in the mass of pharmaceutical excipients, moistening the mass with water or a solvent, drying and fracturing the mass in the particle size within the same size range as described above for the inert nuclei. This can be done through an extrusion and marmerization process. The core of the granule can be prepared by mixing the fluoxetine with conventional pharmaceutical ingredients to obtain the desired concentration and forming the mixture within the cores of desired size by conventional methods or by the. procedure of R.E. Sparks, Y. cabbage. U.S. Patent 5,019,302 and 5,100,592, incorporated herein by reference. A separation layer between the fluoxetine containing the core and the enteric layer is not required, but it is a preferred feature of the formulation. The functions of the separation layer are, if required, to provide a smooth base for the application of the enteric layer, to prolong the resistance of the granule to the acidic conditions and to improve the stability, inhibiting any interaction between the drug and the enteric polymer in the enteric layer. The smoothing function of the separation layer is purely mechanical, the purpose of which is to improve the coating of the enteric layer and avoid fine markings on it, caused by dents and irregularities in the core. Therefore, the more smoothed and free of irregularities the core can be made, the less material is needed in the separation layer and the need for the smoothing characteristic of the separation layer will be completely avoided when the fluoxetine is of a particle size. extremely thin and the core is made as close as possible to truly spherical. . It has been found that when a "pharmaceutically acceptable" non-reducing sugar is added to the separation layer, the strength of the granule to the acidic conditions increases markedly and surprisingly, therefore, such sugar can be included in the separation layer. applied to the cores, either as a powder mix, or dissolved as part of the spray liquid.The separation layer containing the sugar can reduce the amount of enteric polymer that is required to obtain the given level of acid resistance. The cost of the present formulated product is considerably reduced The use of less enteric polymer reduces both the cost of materials and the processing time as well as the amount of polymer available to react with fluoxetine The inhibition of any core / enteric layer interaction is mechanical The separation layer physically prevents the components in the nucleus and the enteric layers from entering Direct contact with each other. In some cases, the separation layer may also act as a diffusion barrier for the migrating core or the enteric layer components dissolved in the wet product. The separation layer can also be used as a light barrier by opacifying it with agents such as titanium dioxide, iron oxides and the like. In general, the separation layer is composed of coherent or polymeric materials, and finely powdered solid excipients which constitute fillers. "When a sugar is used in the separation layer, it is applied in the form of an aqueous solution and constitutes part or all of the coherent material that simultaneously pastes the separation layer, in addition to or instead of sugar, it can be used in the layer For example, substances such as hydroxypropylmethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose and the like can be used in small amounts to increase the adhesion and coherence of the separation layer, it is also advisable to use a filler excipient in the separation layer. to increase the smoothness and solidity of the layer, substances such as finely powdered talc, silicon dioxide and the like are universally accepted as pharmaceutical excipients and can be added as long as convenient in the circumstances of filling and smoothing the separation layer. , when using a sugar, the amount of sugar in the separation layer can It may be in the range of from about 2% to about 10% of the product, and the amount of the polymeric material or other tacky material may be in the range of about 0.1 to about 5%. The amount of filler product, such as talc, would be in the range of from about 5 to about 15%, based on the final weight of the product. "The separation layer can be applied, by spraying aqueous solutions of the sugar or polymeric material and sprinkling in the filling material as described in the preparation of the fluoxetine layer. and homogeneity of the separation layer can be improved, however, if the filler material is completely dispersed as a suspension in the sugar solution and / or polymeric material, and the suspension is sprayed onto the core and dried, using a equipment as described above in the preparation of the nuclei with fluoxetine layers The enteric layer comprises an enteric polymer, which will be chosen for its compatibility with fluoxetine, as discussed above.The polymer can be one having only one small number of carboxylic acid groups per unit weight or repeating polymer units The preferred enteric polymer is succinate acetate hydroxypropylmethylcellulose (HPMCAS), whose product is defined as containing not less than 4% and not more than 28% succinoyl groups, which are the only free carboxyl groups in the compound. See Japanese Standards of Pharmaceutical Ingredients 1991, pages 1216-21, Standard No. 19026. HPMCAS is available from Shin-Etsu Chemical Co., Ltd., Tokyo, Japan, under the trademark of AQOAT. It is available in two grades of particle size and three molecular weight ranges. The L grade, which has an average molecular weight of 93,000 is used in the present examples but other grades are expected to be usable. Enteric polymer coatings can be applied from aqueous suspensions, from solutions in aqueous or organic solvents, or as a powder. The application from organic solvents is currently not favored at all in the pharmaceutical industry, due to the cost of the solvent and the difficulty is in the disposal of solvent vapors or the recovery of the evaporated solvent. Therefore, a detailed discussion of the application of the enteric layer of organic solvents will not be given here, but the pharmaceutical scientist will recognize that such an application is entirely possible if circumstances favor it. The enteric polymer can also be applied according to the method described by Shin-Etsu Co. Ltd. (Obara, et al., Poster PT6115, AAPS Annual Meeting, Seattle, WA, October 27-31, 1996). When an enteric polymer is applied as a powder, the enteric polymer in the solid state is directly added to the tablets or granules while simultaneously spraying the plasticizer onto the tablets or granules. The deposit of solid enteric particles is then transformed into a film by curing. The curing is done by spraying the tablets or granules with a small amount of water and then heating the tablets or granules for a short time.This method of application of enteric coating using the same type of equipment as described above in the preparation of nuclei with fluoxetine layers When the enteric polymer is applied as an aqueous suspension, it is often a problem to obtain a uniform, coherent film.It is highly advisable, therefore, to acquire a fine particle grade or to crush the particles It is possible to either crush the dry polymer, such as in an air impact mill, or prepare the suspension and crush the polymer in the form of a suspension.The crushed suspension is generally preferred, particularly since it can also be used to crush the filling product portion of the enteric layer in the same step. It is convenient to reduce the average particle size of the enteric polymer in the range from about 1 μm to about 5 μm, preferably not more than 3 μm. When the enteric polymer is applied as a suspension, it is important to ensure that the suspension is homogeneous, and that these conditions that favor the agglomeration of the polymer do not occur. Such precautions include the maintenance of the suspension in a condition of gentle agitation, but not agitation so vigorous as to create foam and ensure that the suspension is not held still in eddies, for example, in the bodies of the cannula, or in a pipeline. too large feed. Frequently the polymers in suspension form will agglomerate if the suspension becomes too hot, and the critical temperature can be as low as 30 ° C in individual cases. Since the spray canulas and the tubing are exposed to hot air in the usual fluid bed type equipment, care must be taken to ensure that the suspension is continued to move vigorously through the equipment to cool the tubing and cannula. When using HPMCAS in particular, it is advisable to cool the suspension below 20 ° C before application, cool the tubing and cannula by pumping some cold water through it before starting to pump the suspension, and use a tubing Supply with a diameter as small as the speed of the spray will allow the suspension to continue moving quickly in the pipeline. In the present invention it is preferred, however, to apply the enteric polymer as an aqueous solution whenever possible. In the case of HPMCAS, the dissolution of the polymer can be obtained by neutralizing the polymer, preferably with ammonia. The neutralization of the polymer can be obtained by simply adding ammonia, preferably in the form of aqueous ammonium hydroxide, to a suspension of the polymer in water.; complete neutralization results in complete dissolution of the polymer at a pH of about 5.7-5.9. Good results are also obtained when the polymer is partially neutralized, adding less than the equivalent amount of ammonia. In such a case, the polymer that has not been neutralized remains in suspended form, suspended in a solution of the neutralized polymer. As indicated above, it is obviously important to control the particle size of the polymer when said method is used. The use of the neutralized polymer more readily provides a smooth, coherent enteric layer than when using a suspended polymer, and the use of a partially neutralized polymer provides intermediate steps of smoothness and coherence. Particularly when the enteric layer is applied under a very smooth separation layer, excellent results are obtained from partially neutralized enteric polymers. The extent of the neutralization can be varied over a range without adversely affecting the results or operation totality. For example, an operation with about 25% to about 100% neutralization is preferred in the present invention. Another preferred condition is from about 45% to about 100% metralization, and another preferred condition is from about 65% to about 100%. Yet another preferred way of neutralization is still from about 25% to about 65% neutralized. However, it has been found that the enteric polymer in the resulting product, after drying, is neutralized to a lesser degree than when applied. When neutralized or partially neutralized HPMCAS is applied, the HPMCAS in the final product is from about 0% to about 25% neutralized, more preferably from about 0% to about 15% neutralized. Most enteric polymers require the addition of a plasticizer for best results. In the case of HPMCAS, the preferred plasticizer is triethyl citrate, used in an amount up to about 15% -30% of the amount of the enteric polymer in the application as an aqueous suspension. When neutralized HPMCAS is employed, lower levels of plasticizer may or may not be required. Commonly, minor ingredients are also used, such as defoamers, suspending agents when the polymer is in the suspended form, and surfactants are often also used to aid in the smoothness of the film. For example, up to 1% of the product, silicone defoamers, surfactants such as polysorbate 80, sodium lauryl sulfate and the like, and suspending agents such as carboxymethylcellulose, vegetable gums can frequently be used in amounts in a general range up to 1% of the product. and similar. Usually, the enteric layer is filled with powdered excipients such as talc, glyceryl monostearate or hydrated silicon dioxide to increase the thickness of the layer, strengthen it, reduce the static charge and reduce the cohesion of the particle. Amounts of such solids in a range of from about 1% to about 10% of the final product may be added to the enteric polymer mixture, while the amount of the enteric polymer itself is frequently in the inter-locus of about 5% up to about 25%, more preferably, from about 10% to about 20%. The application of the enteric layer to the granules follows the same general procedure discussed previously, using a fluid bed type equipment with simultaneous spraying of the solution or suspension of the enteric polymer and drying with hot air. The temperature of the drying air and the temperature of the circulating mass of granules should be maintained within the ranges indicated by the manufacturer of the enteric polymer. A termination layer on the enteric layer is not necessary in all cases, but often improves the elegance of the product and its handling, storage and machinability, and can also provide additional benefits. The simplest finishing layer is simply a small amount, approximately less than 1% of an anti-static ingredient such as talc or silicon dioxide, simply sprinkled on the surface of the granules. Another layer of simple termination is a small amount, approximately 1%, of a wax such as beeswax, melted in the circulating mass of granules for an additional smoothing of the granules, reducing the static charge, avoiding any tendency of the granules to stick to each other, and increase the hydrophobicity of the surface. More complex finishing layers can constitute a final spray on the ingredient layer. For example, a thin layer of polymeric material such as hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like may be applied in an amount such as from about 2% to about 10%. The polymeric material may also carry a suspension of an opacifier, a filler ingredient such as a talc, or a coloring material, particularly a finely divided opaque coloring agent such as red or yellow iron oxide. Such a layer dissolves rapidly in the stomach, leaving the enteric layer to protect the fluoxetyria, but provides the product with an additional measure of pharmaceutical elegance and protection against mechanical damage. The finishing layers to be applied to the present product are essentially of the same types as those frequently used in pharmaceutical science for smoothing, sealing and coloring enteric products, and can be formulated and applied in the usual manners. The following Examples establish the preparation of several different enteric granules within the concept of the present invention. The examples also aim to inform the reader about the current enteric granules and their manufacturing methods; Additional variations within the concept of the invention will be clear to the pharmaceutical scientist and their preparation will be within the competence of the scientist. For each example, a list of materials will be given first, which will be expressed in terms of the amount of each ingredient used to prepare a single dose of the granules. Following the list of materials, the procedure will be described, giving the equipment and the size of the batch used in the various stages of manufacture.

Example 1 90 mg Fluoxetine Base / capsule List of Materials Small nuclei sucrose-starch tablets, 30-35 mesh 134, 15 rrg Fluoxetine layer Fluoxet ina 100.58 rrg Sucrose 25,72 rrg Hydroxypropyl methylcellulose 12.89 mg Separation Hydroxypropylmethylcellulose 9,45 rrg Sucrose 28,24 rrg Talc, 500 mesh 50,21 rrg Enteric layer HPCAS -LF 65.66 rrg Triethyl citrate 13.14 rrg Talc, 500 mesh 19, 66 rrg Finishing Coat White mixture (HPMC + dioxide of 43.02 rrg titanium HPMC 10.78 rrg Talc Trace 513, 50 rrg The fluoxetine layer was made by suspending 25% P / P fluoxetine hydrochloride in a binder solution consisting of 6.4% W / W sucrose and 3.2% W / W hydroxypropylmethylcellulose (HPMC). The resulting suspension was then passed through a Coball Mill (Fryma Maschineñ AG, Rheinfelden, Switzerland) model MS-12 to reduce the particle size of the bulk drug. The milled suspension was applied to 1.5 kg of small colored lozenges of sucrose starch in a dry fluid bed dryer that had been fitted with a Wurster column. Upon completion of the application of the desired amount of the fluoxetine hydrochloride suspension, the granules of the fluoxetine core were completely dried in the fluid bed dryer. The separation layer, consisting of 12% P / P talc, 6.75% P / P sucrose and 2.25% hydroxypropyl methylcellulose P / P, was applied to the core of the fluoxetine granules. P. After completing the application of the desired amount of suspension, the granules were completely dried in the fluid bed dryer.

The aqueous suspension of the enteric coating consisting of hydroxypropyl methylcellulose acetate succinate type LF at 6% W / W, 1.8% W / W talc, 1.2% W / W triethyl citrate was completely neutralized by the addition of the 0.47% W / W of ammonium hydroxide. This enteric coating suspension was applied to the fluoxetine separation layer of the coated granules. After completing the application of the desired amount of enteric coating suspension, the granules were completely dried in a fluid bed dryer and a small amount of talc was added to reduce the static charge. A finishing layer was then applied which consisted of a white mixture (composed of titanium dioxide and hydroxypropyl methylcellulose) at 8% W / W and hydroxypropyl methylcellulose at 2% W / W. After completing the application of the desired amount of the colored coating suspension, the granules were fully loaded into the fluid bed dryer and a small amount of talc was added to reduce the static charge. The content of fluoxetine was analyzed in the resulting granules and poured into capsules to provide 90 mg of fluoxetine base.

Example 2 90 mg of Fluoxetine base / capsule List of Materials Small cores of Sucrose-starch, 3 0-35 mesh 134.19 rrg Fluoxetine layer Fluoxetine hydrochloride 100.62 rrg Sucrose 25,77 rrg Hydroxypropylmethylcellulose 12.89 rrg Separation layer Hydroxypropylmethylcellulose 6.12 rrg Sucrose 18,27 rrg Talc, 500 mesh 32,49 rrg Enteric layer HPMCAS -LF 74.89 rrg Triethyl citrate 14.96 rrg Talc, 500 mesh 21,77 rrg Finishing Layer White mixture (HPMC + 43.02 rrg titanium dioxide) HPMC 10.78 rrg Talc Trace 493.65 rrg The product was made substantially in accordance with the procedure used in Example 1.

Example 3 90 mg of Fluoxetine base / capsule List of Materials Small nuclei colored colored Sucrose-starch tablets, 30-35 mesh 121.01 rrg Fluoxetine layer Fluoxetine hydrochloride 100.60 rrg Sucrose 25,75 rrg Hydroxypropylmethylcellulose 12.85 rrg Separation layer Hydroxypropylmethylcellulose 9.48 rrg Sucrose 28.38 rrg Talc, 500 mesh 50,45 rrg Enteric layer HPMCAS - LF 66.78 rrg Triethyl citrate 13.36 rrg Talc, 500 of 20 mesh, 01 rrg Finishing Coat White mixture (HPMC + 44.30 rrg titanium dioxide) HPMC 11.09 rrg Talc Trace 504.06 rrg The product was made substantially according to the procedure used in Example 1 with the exception that the process was scaled up and started with kg of small colored lozenges of sucrose starch.

In more general terms, this invention provides a formulation as follows: 90 mg of Fluoxetine base / capsule List of Materials Small nuclei Colored tablets of Sucrose -starch, 30-35 mesh 100-150 mg Fluoxetine layer Fluoxetine hydrochloride 100.5-100.8 rrg Sucrose 20-30 mg Hydroxypropylmethylcellulose 10-15 mg Separation Layer Hydroxypropylmethylcellulose 4-12 mg Sucrose 15-35 mg Talc, 500 mesh 25-60 mg Enteric layer HPCAS-LF 60-90 mg Triethyl citrate 10-20 mg Talc, 500 mesh 15-25 mg Finishing Coating Mixture white (HPMC + 35-55 mg titanium dioxide HPMC 5-15 mg Talc Trace The granules were made according to the above examples, and the gelatin capsules were filled with various batches of said granules, they were thoroughly tested in the usual manner in pharmaceutical science. The results of the stability studies show that the granules and capsules have sufficient stability during storage to be distributed, marketed and used in a conventional pharmaceutical way. Additional studies show that granules and capsules pass conventional assays for enteric protection under the predominant conditions in the stomach.

It is also shown that the granules release their fluoxetine load acceptably fast when subjected to the predominant conditions in the small intestine. Therefore, the present invention has been shown to solve the problems that were previously encountered in the formulation of other fluoxetine granules. The formulation of this invention can be used to treat people suffering from depression (including major depression (single episode, recurrent, melancholic), atypical, dysthymia, subsurface e, agitated, delayed, comorbid with cancer, diabetes, or post-myocardial infarction, Involutional, bipolar disorders, psychotic, endogenous, and reactive depression), obsessive-compulsive disorders or bulimia. In addition, the formulation can be used to treat people suffering from pain (provided alone or in combination with morphine, codeine, or dextropropoxyphene), obsessive-compulsive personality disorders, post-traumatic stress disorders, hypertension, atherosclerosis, anxiety, anorexia nervosa, panic, social phobia, stuttering, sleep disorders, chronic fatigue, Alzheimer's disease, alcoholism, appetite disorders, weight loss, agoraphobia, memory improvement, amnesia, cessation of smoking, withdrawal symptoms nicotine, mood and / or appetite changes associated with premenstrual syndrome, discouraged mood and / or carbohydrate cravings associated with premenstrual syndrome, mood swings, appetite changes or alterations that contribute to recidivism associated with nicotine deprivation , circadian rhythm disorders, personality limit disorders, hypochondriasis, premenstrual syndrome ( PMS), dysphoric disorder of the late luteal phase, premenstrual dysphoric disorder, trichotillomania, symptoms followed by the interruption of other antidepressants, aggressive / intermittent explosive disorders, compulsive gambling, compulsive use, sex addiction, disorders due to the use of psychoactive substances, sexual disorders, schizophrenia, premature ejaculation, or psychiatric symptoms selected from stress, worry, anger, susceptibility to rejection, and lack of physical or mental energy. Although, of course it will be readily understood that the amount of fluoxetine to be administered presently will be determined by a physician, in view of all the relevant circumstances that include the condition to be treated, and the gender, weight, age, and other physical characteristics of the patient, many preferred regimens advocate for the conditions cited above for the use of a dose of 60 to 120 mg of fluoxetine. For example, it is not unusual for a patient to start treatment with 20 mg / day for about 2 months, then switching to a maintenance dose, for example, 60-120 mg (especially 90 mg) once a week. Also, for the treatment, for example, of bulimia, a patient could begin the dosage with 60 mg / day, then remaining later with 90-120 mg / week. The formulation of this invention allows the prescribing physician, the pharmacist to deliver, and the patient to obtain a unique formulation capable of being used at different doses, even during an initial dose titration (eg, increasing from 20 mg per day to 60 or 90). mg per day, or decreasing from 60 mg to 20 mg) or later changing dosing regimens, for example, from an initial therapy to a maintenance therapy. In addition for capsules that only comprise fluoxetine as an active ingredient, a combination of the fluoxetine product, particularly as the hydrochloride salt, can be made with pindolol, as described in European Patent Application Publication 687,472. These active ingredients are generally present in amounts of about 60-120 mg of fluoxetine hydrochloride and 1 to 60 mg of pindolol. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers. Having described the invention as above, property is claimed as contained in the following:

Claims (1)

1. Claims 1 . An enteric granule of fluoxetine, characterized in that it comprises a) a core composed of fluoxetine and one or more pharmaceutically acceptable excipients; b) an optional separation layer; c) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS) and one or more pharmaceutically acceptable excipients; and d) an optional termination layer. 2 . a granule of claim 1, characterized in that the separation layer is present. 3 . A granule of claim 2, characterized in that the separation layer comprises a pharmaceutically acceptable sugar. Four . A granule of claim 3, characterized in that the sugar is sucrose. 5 . m granule of any of claims 1-4, characterized in that the average particle size of fluoxetine is about 50 μm or less. 6 A fragment of any one of Claims 1-5, characterized in that the core comprises an inert core in which foxoxet is deposited as a layer further comprising a pharmaceutically acceptable excipient. ? A granule of any of claims 1-6, characterized in that the HPMCAS is partially neutralized to the level where from about 0% to about 15% of the succinic groups are neutralized. 8. A granule of claim 7, characterized in that the HPMCAS is neutralized with ammonia. 9. A formulation, characterized in that it comprises a plurality of fluoxetine enteric granules of any of claims 1-8. 10. A formulation of claim 9, characterized in that it contains 20-100 mg of fluoxetine (equivalent base). 11. A formulation of claim 9, characterized in that it contains about 80-90 mg of fluoxetine (equivalent base). 12. A formulation of claim 9, characterized in that it contains approximately 90 mg of fluoxetine (equivalent base). 13. A formulation of any of the active ingredients 9-12, characterized in that fluoxetine is present in the form of fluoxetine hydrochloride. 14. A formulation according to any of claims 9-13, characterized in that also coarrendé pindolol. 15. A formulation of claim 9, characterized in that it contains the following: Small colored cores of sucrose-starch, 30-35 mesh 100-150 rrg Fluoxetine layer Fluoxetine hydrochloride 100.5-100.8 rrg Sucrose 20-30 g Hydroxypropylmethylcellulose 10-15 mg Separation Layer Hydroxypropylmethylcellulose 4-12 mg Sucrose 15-35 mg Talc, 500 mesh 25-60 mg Enteric layer HPMCAS -LF 60-90 mg Triethyl citrate 10-20 rg Talc, 500 mesh 15-25 mg Finishing Coating White blend (HPMC + 35-55 mg titanium dioxide) HPMC 5-15 TQ Talc Trace 16. A gelatin capsule, characterized in that it contains a formulation of any of Claims 9-15. 17. A process for preparing an enteric granule of fluoxetine, characterized in that it comprises: a) administering a nucleus composed of fluoxeti a and one or more pharmaceutically acceptable excipients; b) optionally, applying to the core a separation layer comprising one or more pharmaceutically acceptable excipients; c) applying an enteric layer comprising HPMCAS and one or more pharmaceutically acceptable excipients, wherein HPMCAS is applied as an aqueous solution or suspension and the application takes place in a fluid bed type apparatus; d) optionally, apply a finishing layer. 18. The procedure of claim 17, characterized in that HPMCAS is totally or partially neutralized. 19 The process of claim 18, characterized in that HPMCAS is neutralized to the level where from about 25% to about 100% of the succinic acid groups are neutralized. twenty . a process of claim iß or claim 1, characterized by HPLCAS park is neutralized with ammonia or ammonium hydroxide. 21. A method of any of claims 17-20, characterized in that the core is prepared by applying f luoxetine and one or more pharmaceutically acceptable excipients to an inert core. 22 A method of any of claims 17-21, characterized in that the separation layer is applied. 2. 3 . Uh procedure of claim 22 >; characterized in that the separation layer comprises a pharmaceutically acceptable sugar. 24. The process of claim 23, characterized in that the sugar is sucrose.